Oxytocin (OT) is a neuropeptide that plays an important role in regulating many aspects of social behavior, including maternal nurturing, social information processing, and social attachment. Intranasal administration of OT in humans increases attention to social cues, gazing into the eyes, inferring the emotions of others, trust and socially reinforced learning. Several studies have demonstrated that OT enhances some aspects of social functioning in individuals with autism spectrum disorder (ASD), and the OT system is a potential pharmacological target for enhancing social function in ASD. Furthermore, there is evidence of altered OT systems in ASD, including decreased concentrations of OT in plasma, genetic association between ASD and polymorphisms in the OT receptor gene (OXTR), and reduced OXTR mRNA in the brains of subjects with ASD. Genetic polymorphisms in the OXTR gene have been associated with variation in social cognition in both ASD and healthy subjects. The socially monogamous prairie vole has provided great insights into the role of OT in regulating social behavior. OT acts in the nucleus accumbens (NAcc) to promote alloparental nurturing and pair bonding between mates. Variation in OXTR density in the NAcc is correlated with variation in alloparental behavior and pair bonding. In this project we will explore the contribution of a natural genetic variation in the OXTR gene to social behavior and susceptibility to early-life social stressors. The first aim will determine whether a single nucleotide polymorphism in the prairie vole oxtr gene that predicts OXTR expression in the striatum (e.g. NAcc and caudate putamen) is associated with variation in social behavior in male and female prairie voles at multiple developmental epochs. In the second Aim, we will infuse an shRNA viral vector targeting the Oxtr in the NAcc of high OXTR expressing genotype voles early in development to determine whether OXTR knockdown the NAcc recapitulates the phenotype-genotype relationships observed in Aim 1. The third aim will test the hypothesis that animals with low levels of OXTR in the NAcc are more severely impacted by early-life social deprivation, modeling gene x environment interactions. Finally we will explore the possibility that a pharmacological approach to stimulate OT release can rescue the social deficits generated by the OXTR polymorphism and early-life social deprivation. We will examine three different developmental windows for chronic OT based therapy as well as an acute treatment in adults on partner preference formation. These studies will provide detailed insight into the acute and developmental impact of OXTR signaling on a suite of social behaviors, determine the effect of variation in OXTR expression in brain regions known to regulate social behavior, and begin to explore a potential pharmacological intervention to enhance OXTR signaling in individuals with compromised OXTR function. This work will inform future development of novel therapeutic strategies to enhance social function in ASD and other psychiatric disorders. PUBLIC HEALTH RELEVANCE: The neuropeptide oxytocin enhances social motivation and social attachment in animal models and improves social functioning in humans diagnosed with Autism Spectrum Disorder. This project uses socially monogamous prairie voles to explore the neural mechanisms by which variation in oxytocin receptors affects social behavior. The experiments will provide insights into the consequences of compromised oxytocin systems and may inform novel therapeutic strategies for improving social functioning in autism and other psychiatric disorders.